Genomic characterization of breast cancer in high risk subsets of breast cancer

40岁以下的妇女约占乳腺癌患者的5%，但许多研究表明，她们的预后和预后比年龄较大的妇女更差。来自年轻女性的乳腺肿瘤通常是ER阴性的，来自非洲裔美国人的患者，并且具有其他高风险指标：然而，多变量分析表明，年轻本身是预后不良的独立预测因素。至少部分是由于国防部所服务的患者群体的独特性质，在WRNMMC看到年轻女性乳腺癌病例的不成比例。因此，CBCP招募了大量40岁以下的浸润性乳腺癌患者，使我们有可能提出这项研究。位于Windber研究所的CBCP组织库在OCT中有40个肿瘤，这些肿瘤的生殖系DNA可从这些样本的血凝块中获得。因此，有足够的数量来获得有意义的数据。具有生殖系DNA的肿瘤将进行全外显子组测序和RNAseq。对于没有匹配生殖系DNA的肿瘤，我们将仅进行RNAseq。在资金允许的情况下，我们还将使用Meltzer博士开发的OncoVar测试来评估样本，该测试可以测试已知在实体瘤中经常突变的250多个基因的突变，缺失和易位。基因组分析将与NCI的Paul Meltzer合作完成。这些分析将使我们能够确定在年轻女性肿瘤中观察到的突变谱。基于肿瘤的临床分类（管腔A、管腔B、HER 2+和三阴性），将所有这些样本临床注释为组。对于从WRNMMC入组的患者，大多数病例有结局数据，正在收集更多结局数据。这些分析将与乳腺癌的临床可用数据库（例如TCGA）进行比较，以确定肿瘤是否具有与老年女性或整体乳腺癌中观察到的不同的突变谱或频率。这些数据应该有助于确定年轻女性风险增加的性质，因为这可能是由于肿瘤基因组学的差异，或者如果没有差异，可能是由于肿瘤产生的环境。因此，无论哪种情况，数据都将提供信息。尽管患有乳腺癌的年轻女性预后不良，但几乎没有研究，也没有临床特异性临床试验。该项目及其进一步发展可能是该领域的一个重大进展。目的2：化生性和炎性乳腺癌肿瘤的探索性分析。化生性乳腺癌和炎性乳腺癌是两种罕见的（分别为1%和2- 3%）侵袭性乳腺癌。对于其中的每一种，驱动这些亚型的突变都没有得到很好的表征。不幸的是，由于这种肿瘤的发生率很低，OCT中每种肿瘤只有4例（每种只有3例具有匹配的生殖系DNA），因此该目标是一个探索性目标，我们将如上所述处理肿瘤。对于具有匹配DNA的3个，我们将进行全外显子组测序和RNAseq。对于没有匹配生殖系DNA的样本，我们将仅进行RNAseq。同样，如果资金允许，我们将使用Melzer博士开发的OncoVar检测。现有的样本太少，不能给我们一个真实的疾病谱，但可以想象，确定新的突变，可能是独特的这些子集。我们会与其他机构（例如JHU、WHC）合作，以增加每个机构的样本量，从而扩大这些队列。目的3：对美国国防部数据库中的年轻女性、化生性和炎性乳腺癌进行生物信息学分析。美国国防部在MDR和DoDCCR数据库中有14,588名乳腺癌患者的临床数据，这些患者在1998年至2007年期间在国防部设施接受治疗（未来更新将包括2012年接受治疗的患者）。在军事人口科学和流行病学MCC的Kangmin Zhu博士的合作下，并在WMB的Alexandra Zimmer博士的协助下，我们将使用该数据库调查年轻女性癌症的发病率，并跟踪治疗和结果。如果数量足够，我们也将在化生性和炎性癌症中探讨这些问题。

Women under the age of 40 account for approximately 5% percent of breast cancer patients but numerous studies have shown that they have a worse prognosis and poorer outcome than women diagnosed at older ages. Breast tumors from young women are often ER-negative, from African-American patients and have other indicators of high risk: yet, multivariate analyses demonstrated that young age, in and of itself, is an independent predictor of poor outcome. At least partially due to the unique nature of the patient population served by DOD, a disproportionate number of breast cancer cases in young women are seen at WRNMMC. Thus CBCP has enrolled a good number of invasive breast cancer patients under 40 making it possible for us to propose this study. The CBCP Tissue Bank hosted at the Windber Research Institute has 40 tumors in OCT with germ line DNA available from blood clots for these sample. Thus there are sufficient numbers to get meaningful data. The tumors with germline DNA available will undergo whole exome sequencing and RNAseq. For tumors without matching germline DNA we will perform RNAseq only. We would also, as funding allows, to assess the samples using the OncoVar test developed by Dr. Meltzer which can test for mutation, deletions, and translocations in more than 250 genes known to be frequently mutated in solid tumors. The genomic analysis will be done in collaboration with Paul Meltzer at the NCI. These analyses will allow us to determine the spectrum of mutations seen in tumors from young women. All of these samples are clinically annotated into groups based on the clinical classification of the tumors (Luminal A, Luminal B, HER2+, and triple negative). For patients enrolled from the WRNMMC, most of the cases have outcome data and more outcome data is being collected. These analyses will be compared to the publically available databases for breast cancer (e.g. TCGA) in order to determine if the tumors have a different spectrum or frequency of mutations from those seen in older women or breast cancer as a whole. These data should help define the nature of the increased risk in young women as it could be due to differences in tumor genomics, or if there is no difference, it could be due to the environment in which the tumors arise. Thus the data will be informative in either case. Despite the poor prognosis of young women with breast cancer, little research and no clinical specific clinical trials are available. This project and its further development could represent a major advance in the field. Aim 2; Exploratory analysis of metaplastic and inflammatory breast cancer tumors. Metaplastic and inflammatory breast cancer are two rare (1% and 2-3%, respectively) types of aggressive breast cancer. For each of these, the mutations that drive these subtypes are not well characterized. Unfortunately, due to the low frequency of such tumors, there are only 4 of each of these in OCT (and only 3 of each with matching germline DNA) so that this Aim is an exploratory aim in which we will approach the tumors as above. For the 3 of each with matching DNA we will perform whole exome sequencing and RNAseq. For the samples without matching germline DNA, we will perform only RNAseq. Again, as funding permits we will use the OncoVar assay developed by Dr. Melzer. The existing samples are too few to give us a true spectrum of the diseases but could conceivable identify novel mutations that might be unique to these subsets. We will seek to expand these cohorts through collaboration with other institutions (e.g. JHU, WHC) to increase the sample size of each. Aim 3: Bioinformatic analysis of young women, metaplastic, and inflammatory breast cancer in the DOD databases. The DOD has clinical data in the linked MDR and DoDCCR databases on 14,588 breast cancer patients treated at DOD facilities between 1998-2007 (with future updates to include those treated through 2012). In collaboration with Dr. Kangmin Zhu at the MCC for Military Population Sciences and Epidemiology and assisted by Dr. Alexandra Zimmer from the WMB, we will use the database to investigate the incidence of the cancers in young women and track treatment and outcomes. If the numbers are sufficient, we will also explore these questions in metaplastic, and inflammatory cancers.